The association between psychosocial factors and systemic lupus erythematosus (SLE) is still a matter of discussion. Mood disorders may represent neuropsychiatric manifestations of SLE disease activity or may be a consequence of the stress of having a chronic major disease. We examined the hypothesis that SLE disease activity is related to the presence and severity of major depression in patients with SLE. Seventy-one patients with SLE were evaluated for the presence and intensity of major depressive disorder, psychosocial stressors, functional disability, SLE disease activity, and cumulative damage. Patients with major depression presented a trend toward having greater severity of SLE disease activity compared with those without major depression (P = .056). Major depression was also associated with life events (P = .017) and hassles (P < .001). Reinforcing these findings, depression severity was directly correlated with disease activity (r = 0.26, P = .026) and with functional disability (r = 0.46, P < .001). Moreover, multiple linear regression analysis, controlling for stressful life events and previous major depressive episodes, demonstrated that SLE disease activity still was associated with depression severity (P = .014). In conclusion, these results support the hypothesis that SLE disease activity is a potential risk factor for the presence and severity of major depression in patients with SLE. Whether major depression in active SLE is a central nervous system manifestation of the disease that is mediated by an autoimmune mechanism deserves further research.